TY - JOUR
T1 - Silent synapses dictate cocaine memory destabilization and reconsolidation
AU - Wright, William J.
AU - Graziane, Nicholas M.
AU - Neumann, Peter A.
AU - Hamilton, Peter J.
AU - Cates, Hannah M.
AU - Fuerst, Lauren
AU - Spenceley, Alexander
AU - MacKinnon-Booth, Natalie
AU - Iyer, Kartik
AU - Huang, Yanhua H.
AU - Shaham, Yavin
AU - Schlüter, Oliver M.
AU - Nestler, Eric J.
AU - Dong, Yan
N1 - Funding Information:
1Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA. 2Departments of Anesthesiology and Perioperative Medicine and Pharmacology, Penn State College of Medicine, Hershey, PA, USA. 3Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 4Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. 5Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA. 6These authors contributed equally: William J. Wright, Nicholas M. Graziane. *e-mail: yandong@pitt.edu
Funding Information:
We thank K. Tang and K. Churn for excellent technical support, as well as M. Varkey, M. Mulloth, S. Beriwal, S. Maddukkuri, Y. Jung, O. Ikwuegbu, R. Moazzam and A. Kang for assistance with behavioral training. This work was supported by NIH grant nos. NS007433 (W.J.W.), DA043940 (W.J.W.), DA023206 (Y.D.), DA044538 (Y.D.), DA040620 (Y.D., E.J.N.), DA047861 (Y.D.), DA035805 (Y.H.H.), MH101147 (Y.H.H.), DA008227 (E.J.N.) and DA014133 (E.J.N.); the NIDA Intramural Research Program (Y.S.); and a Mellon Fellowship (W.J.W.).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.
AB - Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.
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UR - http://www.scopus.com/inward/citedby.url?scp=85075924796&partnerID=8YFLogxK
U2 - 10.1038/s41593-019-0537-6
DO - 10.1038/s41593-019-0537-6
M3 - Article
C2 - 31792465
AN - SCOPUS:85075924796
SN - 1097-6256
VL - 23
SP - 32
EP - 46
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 1
ER -